Context: The Melanin Concentrating Hormone Receptor 2 (MCHR2) is a G protein-coupled receptor for MCH, a neuropeptide that plays important role in feeding behaviors. MCHR2 maps on chromosome 6q16.3, in a susceptibility locus for childhood obesity. Objective: The aim of this study was to investigate the association between MCHR2 variation and human obesity. Design: Case control and family-based studies were performed. Participants: 141 obese children and 24 non-obese adult subjects were sequenced and case-control analyses were conducted using 628 severely obese children and 1,401 controls. Results: Eleven Single Nucleotide Polymorphisms (SNPs) were identified. We showed nominal association between -38,245 ATG A/G SNP (p=0.03, 95%CI=[1.02–1.34], OR=1.17), A76A T/C SNP (p=0.03, 95%CI=[0.58–0.97], OR=0.75) and childhood obesity. Analysis of 645 trios with childhood obesity supported further the A76A T/C association, showing an over-transmission to obese children of the at risk T allele (59.0%, p=0.01), especially in children with most severe forms of obesity (Zscore of BMI>4) (67.0%, p=0.003). The A76A at risk T allele was also associated with overeating during meal (p=0.02) in an additional group of 102 non-obese children. None of MCHR2 variants, including the A76A SNP, showed association with adult severe obesity, although a trend for association of the T allele of this variant with food disinhibition (p=0.06) and higher hunger (p=0.09) was found. This variant was not associated with childhood obesity in an independent case-control study including 1,573 subjects (p=0.98). Moreover, the A76A SNP did not explain the linkage on the 6q locus. Conclusions: Our results altogether suggest that MCHR2 is not a major contributor to polygenic obesity and support a modest effect of the A76A SNP on food intake abnormalities in childhood.